The objective of the proposed research is to develop an ultrasonic, radiation-force based imaging system capable of locally quantifying the shear modulus of soft tissues throughout a 2D Field of View (FOV), and to investigate its utility in the context of staging liver fibrosis. This system will build upon technology that has been developed during the first funding cycle (Acoustic Radiation Force Impulse (2D-ARFI) imaging), and will provide co-registered B-mode and quantitative stiffness images over a large FOV. We have developed robust, quantitative shear modulus reconstruction methods based upon ultrasonically monitoring tissues'responses to localized radiation force excitations. We have validated these methods in calibrated tissue mimicking phantoms and have performed initial clinical studies using these reconstruction methods to quantify the shear modulus of the livers of healthy volunteers. In this proposal, we will optimize these methods and investigate their ability to stage and quantify liver fibrosis. Over 25,000,000 Americans have experienced liver disease. Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common liver disease in the western world and is approaching epidemic proportions as obesity becomes a significant medical dilemma. NAFLD is the hepatic manifestation of metabolic syndrome (obesity, hyperinsulinemia, dyslipidemia, hypertension) in which lipid accumulates in hepatocytes. NAFLD patients can progress to Non-Alcoholic Steatohepatitis (NASH, i.e. inflammatory hepatic steatosis), progressive fibrosis, cirrhosis (i.e. extensive fibrotic scarring throughout the liver), and end-stage liver disease (decompensated cirrhosis). Treatment of the majority of liver diseases, including NAFLD and chronic hepatitis, is dictated by the extent of fibrosis throughout the liver, as determined by liver biopsy and liver function using blood serum markers. Unfortunately, blood serum markers are not specific for liver decompensation, and liver biopsy samples are associated with inaccurate fibrosis evaluation since they are typically limited to a single needle core (18-25 mm in length, 14-18 gauge needle). We hypothesize that: 1) our proposed imaging system will be capable of quantifying changes in liver stiffness (i.e. shear modulus), 2) these stiffness changes will be correlated with histologically determined fibrosis stage, and 3) the 2D nature of our method will increase the accuracy of fibrosis staging as compared to the clinical standard of a single core needle biopsy. Due to its noninvasive and inexpensive nature, this system will provide the currently unavailable ability to longitudinally track fibrotic hepatic disease progression and monitor the liver's response to treatment protocols. We have initiated development of and propose to expand custom beam sequences and robust data processing algorithms to provide shear modulus estimates throughout a 2D FOV, with resolution approaching 3x3 mm, to be overlaid on co-registered B-mode images. We have obtained initial data in rat liver in vivo, and propose studies in a known chronic liver disease/fibrosis rat model to investigate the correlation between fibrosis score, histology, and our stiffness metric. We have also obtained preliminary data in human volunteers in vivo, and we propose an in vivo human study in which our stiffness metric will be correlated with biopsy findings. Upon completion of these studies, we will have 1) developed a noninvasive method of hepatic fibrosis stiffness scoring and monitoring over a large region of the liver for both human and small animal imaging, 2) determined the correlation between the fibrosis stiffness metric and histologic fibrosis stage, 3) demonstrated the system's feasibility in a small human clinical study, and 4) be in position to perform a large follow-on clinical study of the method's utility for liver disease staging and treatment monitoring.